Like many common diseases, autoimmune disorders generally result from a complex mix of pathogenic[unreadable] factors that are environmental and genetic in nature. Among these factors, are likely to be processes that[unreadable] govern the control of immune tolerance which can be broadly separated into central and peripheral tolerance[unreadable] mechanisms. Until recently, however, the role of central tolerance in the pathogenesis of autoimmune[unreadable] disease was unclear. Our laboratory group and others have uncovered a direct link between autoimmunity[unreadable] and central tolerance through the detailed study of the AIRE (for AutolmmuneRegulator) gene. This gene[unreadable] was originally identified through the study of patients with the clinical autoimmune disorder APECED. These[unreadable] patients develop multi-organ autoimmunity, mainly involving the endocrine organs. We have generated[unreadable] AIRE-deficient mice and our previous work with these animals has demonstrated that these animals have a[unreadable] defect in the ability of the thymus to tolerize developing T cells to self-antigens whose expression is[unreadable] controlled by AIRE. This finding has helped establish that central tolerance in the thymus is important in the[unreadable] prevention of autoimmune disease and has provoked us to hypothesize how the central tolerance defect[unreadable] present in these animals interacts with other modifying factors and that this process can be used as a tool to[unreadable] prevent autoimmune disease.[unreadable] This work has important implications for the more detailed understanding of how autoimmune disease(s)[unreadable] occur and how they can be prevented. The model system that is utilized in these studies has a direct link to[unreadable] an existing clinical disorder whose symptoms include autoimmunity to the pancreatic islets, thyroid, adrenal,[unreadable] parathyroid, and liver. The proposed work is designed to learn more about how these important diseases[unreadable] unfold and also how they can potentially be prevented.